WO2002038546A1 - Derives de bis-indole substitue utilises comme agents de contraste, compositions pharmaceutiques contenant lesdits derives et intermediaires permettant de preparer ces derives - Google Patents

Derives de bis-indole substitue utilises comme agents de contraste, compositions pharmaceutiques contenant lesdits derives et intermediaires permettant de preparer ces derives Download PDF

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WO2002038546A1
WO2002038546A1 PCT/BE2001/000192 BE0100192W WO0238546A1 WO 2002038546 A1 WO2002038546 A1 WO 2002038546A1 BE 0100192 W BE0100192 W BE 0100192W WO 0238546 A1 WO0238546 A1 WO 0238546A1
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bis
metal
indole
acid
complexable
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PCT/BE2001/000192
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English (en)
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Erwin Cresens
Yicheng Ni
Paul Adriaens
Alfons Verbruggen
Guy Marchal
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K.U. Leuven Research & Development
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Priority claimed from GB0027249A external-priority patent/GB2368843A/en
Priority claimed from GB0120659A external-priority patent/GB0120659D0/en
Application filed by K.U. Leuven Research & Development filed Critical K.U. Leuven Research & Development
Priority to EP01993601A priority Critical patent/EP1343758A1/fr
Priority to AU2002218075A priority patent/AU2002218075A1/en
Priority to US10/416,043 priority patent/US7081472B2/en
Publication of WO2002038546A1 publication Critical patent/WO2002038546A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/122—Macromolecular compounds dimers of complexes or complex-forming compounds

Definitions

  • the present invention relates to a novel class of bis-indole derivatives useful as tools in biochemical, biomedical and medical applications.
  • the present invention relates to the use of these novel compounds or pharmaceutically acceptable salts and formulations thereof in therapeutic and/or diagnostic applications, in particular as contrast agents for the identification and visualization of tissues and organs. More particularly, certain such compounds are useful for the identification and visualization of necrosis and necrosis related diseases including myocardial and cerebral infarction.
  • the present invention also relates to methods for preparing such bis-indole derivatives, as well as intermediates therefore.
  • 5,808,064 further discloses 2,3-disubstituted indoles wherein the 2-substituent is a trialkylsilyl or triphenylsilyl group.
  • U.S. Patent No. 5,877,329 discloses 2,3,5-trisubstituted indoles being useful intermediates in preparing biologically active compounds such as certain lipoxygenase inhibitors.
  • U.S. Patent No. 5,932,743 discloses 2,3-disubstituted indole-6-carboxylic acids having estrogen agonist activity.
  • EP-A-887.348 additionally discloses substituted [bis-indol-3-yl)methyI] benzenes wherein the phenyl group of the indole linking bridge is substituted with hydroxy or carboxy, and wherein the phenyl rings of the indole groups are symmetrically substituted in the 5-position or 6-position with hydroxy, bromo, amino, methylamino, diethylamino, isopropyl or ethylthio, these compounds being useful as antitumor and antimetastatic agents.
  • 2,2'-di(C ⁇ -C 5 )alkyl-3 I 3'-diindolylmethanes I 1 , 1 '-di(C ⁇ -C 5 )alkyl-3,3'- diindolyl-methanes, 5,5'-dihalo-3,3'-diindolylmethanes, 5,5'-di(C ⁇ -C 5 )alkyl-3,3'- diindolyl-methanes and 5,5'-di(C ⁇ -C 5 )alkoxy-3,3'-diindolylmethanes.
  • a preferred synthesis in three steps consists of first forming a substituted indole-3-aldehyde, then reducing it into the corresponding substituted indole-3-methanol which is then condensed for example by treatment with a phosphate buffer having a pH around 5.5.
  • Some of these compounds such as the gadolinium complex of a bis-diethylenetriaminepentaacetic acid pamoic acid derivative obtained from 3-hydroxy-2-naphtalene methyl carboxylate through its reaction with hydrazine, exhibit a unique targetability to necrotic tissues.
  • Such pamoic acid derivatives however exhibit some shortcomings.
  • solutions of these compounds with concentrations useful for medical applications are not colorless and, during long term storage, may encounter significant discoloration of pharmaceutical preparations containing them.
  • a 0.25 mmolar solution of the said gadolinium complex of the bis-diethylenetriaminepentaacetic acid pamoic acid derivative obtained from 3-hydroxy-2-naphtalene methyl carboxylate has a yellow-orange color and has an absorbance of 0.75 at 400 nm.
  • significant side effects e.g. myocarditis
  • myocarditis were observed in animals having received an intravenous bolus injection of 1 mmole of the said gadolinium complex per kg body weight.
  • the state of the art provides six different classes of disubstituted bis-indoles, being respectively the symmetrical 1 ,3-disubstitution, 2,3-disubstitution, 2,5-disubstitution, 3,5-disubstitution and 3,6-disubstitution and the disymmetrical 2,2',3,5'-substitution of a bis-indolyl basic structure.
  • 1,2- and 2,4- disubstituted indoles are also respectively available, which could in principle be condensed, using coupling procedures standard in the art, in order to achieve the corresponding disubstituted bis-indoles.
  • the bis-indoles bearing carboxylic acid ester substituents described so far are either symmetrical 2,5-disubstituted bis-indoles or the disymmetrical 2,2',3,5'- substituted bis-indoles.
  • contrast agents in particular multipurpose contrast agents and tissue-specific contrast agents which would be in vivo effective for the identification, localization and therapeutic follow-up of pathological tissue disorders, in particular those resulting from ischemic diseases and space-occupying lesions, including necrosis, but which would not suffer from the above-mentioned drawbacks (significant discoloration upon long-term storage, myocardial toxicity) of the pamoic acid derivatives known in the art.
  • compositions including tissue-specific and/or multipurpose contrast agents which are suitable for use in magnetic resonance imaging and nuclear scintigraphy imaging technologies while requiring only low doses of the active agent. It is therefore the goal of the present invention to provide useful compounds meeting these various criteria, as well as a suitable and cost- effective manufacturing route for their synthesis.
  • the present invention provides new and useful compounds having one of the formulae (I), (la) and (lb) as specified hereinafter, as well as methods for making them.
  • the compounds of general formula (I) are useful as vectors and agents in therapy and medical diagnosis.
  • the invention provides compositions, use and methods for use comprising the compounds having formula (I).
  • the present invention is mainly based on the unexpected finding that useful metal-complexable compounds may be obtained by first preparing 2,3- disubstituted bis-indoles starting materials preferably bearing at least one carboxylic acid reactive substituent (such as acid, acid halide or acid ester) that is able either to directly condense with at least a suitable chelating agent or to react with a spacing agent such as a bis-amine or an amino-acid in order to achieve precursor compounds such as bis(indolecarboxylic acid hydrazides and analogues thereof which themselves are able to condense with at least a suitable chelating agent.
  • carboxylic acid reactive substituent such as acid, acid halide or acid ester
  • the substituted bis-indole derivatives thus produced, as well as their enantiomers and their pharmaceutically acceptable salts, are able to form complexes with radioactive and non-radioactive metals.
  • the metal- complexable substituted bis-indole derivatives and the metal complexes obtained therefrom constitute the active ingredients of pharmaceutical compositions which are useful, among others, in the diagnosis or therapy of ischemic diseases or space-occupying lesions in a patient, for instance for imaging a tissue in a mammal, or as a necrosis-avid agent or as a multipurpose contrast agent for various organs or parts of organs of a mammalian body, wherein the multipurpose function includes at least one of a blood pool agent, a liver agent and a kidney agent.
  • the present invention also relates to a method for generating an image of at least a part of the body of a mammal, comprising systemically or locally administering to the said mammal a contrast agent effective amount of such a metal-complexable substituted bis-indole derivative or a metal complex or a pharmaceutically acceptable salt thereof.
  • Figure 1 schematically shows a synthesis procedure to obtain mono- reactive anhydride bifunctional chelating agents which are useful in preparing the metal-complexable bis-indole derivatives of the invention.
  • Figure 2 shows the detailed formula of one exemplary metal- complexable bis-indole derivative according to the invention (the compound of example 8).
  • Figure 3 (A-D) illustrates the necrosis contrast agent function of one exemplary metal-complexable bis-indole derivative according to the invention by showing photographs of magnetic resonance images (MRI) obtained in a rat model of experimentally induced reperfused liver infarction before (A) and after (B-D) intravenous injection of the compound of examples 8.
  • Figure 3E shows a photograph of a macroscopic histological slice corresponding to the same MRI image, obtained after sacrificing the same rat (arrows indicate necrotic liver lobe, S stands for stomach).
  • Figure 4 illustrates the necrosis contrast agent function of one exemplary metal-complexable bis-indole derivative according to the invention by showing magnetic resonance images of a pig with reperfused myocardial infrarction before (A) and after (B-C) intravenous injection of the compound of example 8.
  • Figure 4D shows a photograph of a heart section of the same pig.
  • Figure 5 shows magnetic resonance angiographic images of a rabbit after intravenous injection of a commercial contrast agent Gd-DTPA (A-C) as a comparative example, and (A'-C) after intravenous injection of one exemplary metal-complexable bis-indole derivative according to the invention (the compound of example 8).
  • A-C commercial contrast agent Gd-DTPA
  • Figure 6 (A-E) shows magnetic resonance images of a rat with liver implantation of rhabdomyocarcoma treated with radiofrequency ablation before
  • Figure 6F shows a photograph of a histological cross- section of the same rat.
  • metal- complexable substituted bis-indole derivatives comprising the structure shown in formula (I) hereunder:
  • - L represents a single bond or an optionally substituted linking agent (Li) which covalently links together the carbon atoms being respectively in positions 2 or 3 and 2' or 3' on the heterocyclic rings of the indolyl groups;
  • R 2 are optional substituents of any free position of the phenyl rings of the indolyl groups
  • - q, p and r are integers indicating the number of the respective substituents Ri, R 2 and R 3 , provided that r is 0 when L is a single bond;
  • Ci and C 2 are optional metal-complexing substituents of the heterocyclic rings of the indolyl groups
  • - m and n are integers indicating the number of the respective metal- complexing substituents Ci and C 2 and are each 0 or 1 , provided that the sum of m and n is at least 1.
  • - m is 1 and n is 1 ; - at least one of m and n is 1 and the metal-complexing substituent Ci or C 2 is in an ⁇ position with respect to the single bond L or linking agent (Li);
  • linking agent (Li) is selected from the group consisting of a bridging at least divalent heteroatom, a disulfide bridge and an optionally substituted alkylene group wherein the alkylene chain may be interrupted by one or more heteroatoms; examples of suitable at least divalent heteroatoms include oxygen and sulfur; when sulfur is used as a heteroatom, (Li) may also be SO or SO 2 ; examples of suitable alkylene groups include methylene, ethylene and straight-chain or branched-chain alkylene groups having from 3 up to 6 carbon atoms (such as trimethylene, tetramethylene or hexamethylene), each hydrogen atom of the said alkylene groups being possibly substituted with an R 3 substituent such as defined hereinbelow in more detail; when the alkylene chain is interrupted by one or more heteroatoms, the latter
  • the linking agent (Li) is a methylene group optionally substituted with one or two substituents R 3 , the said substituents R 3 being preferably non-functional, i.e non reactive with chemical functions born by other parts of the bis-indole derivatives of the invention, in particular by the metal- complexing substituents thereof; - more preferably the linking agent (Li) is a methylene group substituted with one or two substituents R 3 , each substituent R 3 being an optionally substituted aryl or heteroaryl group or an optionally substituted branched chain or straight chain alkyl group having from 1 to 20 carbon atoms, wherein the substituents on the said alkyl, aryl or heteroaryl group are preferably substituents which are not easily oxidable, such as halogen atoms (including fluorine, chlorine, bromine and iodine), saturated or unsaturated hydrocarbon groups having 1 to 4 carbon atoms (in particular alkyl groups such as methyl, e
  • each of p, q and r is independently selected from integers ranging from 0 to about 4.
  • linking agents (Li) being a substituted methylene group may be derived from aliphatic, aromatic or heteroaromatic aldehydes such as (in the following non-exhaustive list, use of the plural is meant to include all possible isomers) benzaldehyde, mono- and polyhalogenated benzaldehydes, cyano- benzaldehydes, substituted or non-substituted aminobenzaldehydes, mono- and dinitro-benzaldehydes, mono- and polyalkoxybenzaldehydes, mono- and polyalkylated benzaldehydes, carboxylated benzaldehydes, aryloxy- benzaldehydes, 2-fluorenecarboxaldehyde, naphthaldehydes, alkoxy- naphthaldehydes, N-ethyl-3-carbazole-carboxaldehyde, 4-formylcinnamic acid,
  • Ci and C 2 metal-complexing substituents are each independently represented by the formula -(Sp) s -CA, wherein CA is a chelating agent, (Sp) is a spacing agent being attached (i.e. covalently linked) both to the heterocyclic ring of the indolyl group and to the chelating agent CA, and s is an integer selected from 0 and 1 (thus meaning that the spacing agent (Sp) is optional in the structure of the metal-complexable bis-indole derivative of the present invention).
  • s may be 0 when an amino substituent is present on a heterocyclic ring of an indolyl group and the chelating agent CA comprises a terminal functional group, such as carboxylic acid, acid halide or acid ester that is able to readily react with the said amino substituent or when an amino substituent is present on the chelating agent CA and a heterocyclic ring of an indolyl group comprises a terminal functional group, such as carboxylic acid, acid halide or acid ester that is able to readily react with the said amino substituent.
  • a heterocyclic ring of an indolyl group comprises a terminal functional group, such as carboxylic acid, acid halide or acid ester that is able to readily react with the said amino substituent.
  • the structure of the chelating agent CA may comprise:
  • thiol bearing moieties such as for example bisamine-bisthiol, bisamine-bisoxime, monomercapto-triamide, diamide-dithiol, monoamine- monoamide-dithiol, tetramine, monoamine-diamide-monothiol, monoamine- monothioether-dithiol, monoamine-monothiol, monoamide-diamine- monothiol and diphosphine based moieties (for reasons of stability of the complex formed with certain metals, this type of chelating agent is preferred namely when the metal is technetium-99m, rhenium-186 or rhenium-188); and/or
  • Z' is a radical selected from the group consisting of phosphonomethyl (-CH 2 PO 3 HR ), carboxymethyl (-CH 2 COOR 4 ) and its derivatives (-CHR 5 COOR 4 ), carboxyethyl (-CH 2 CH 2 COOR 4 ) and its derivatives (-CHR 5 CH 2 COOR 4 and -CH 2 CHR 5 COOR 4 );
  • Z" is hydrogen or a radical in the meaning of Z' or hydroxyethyl -CH 2 CH 2 OH or its derivatives -CHR 5 CH 2 OH and -CH 2 CHR 5 OH), i.e.
  • R 4 is selected from hydrogen and optionally substituted C-i-C 2 o branched chain or straight chain alkyl groups or C6-C 2 o aryl groups or C6-C 2 o alkylaryl groups, wherein the substituents on the alkyl, aryl or alkylaryl group may be for instance halogen atoms (including fluorine, chlorine, iodine and bromine), nitro, carboxy, amino, aminyl, amido or sulfono and wherein the number of such substituents may be from 0 to 3 or even more, depending on the number of carbon atoms of the said group; and R5 is selected from groups in
  • a first class of preferred chelating agents CA may be represented by one of the following formulae:
  • each V independently represents an optionally substituted saturated, unsaturated or aromatic organylene group, such as phenylene, diphenylene, straight-chain or branched-chain hydrocarbylene group wherein the chain or part of it may form a cyclic or heterocyclic ring and wherein the hydrocarbylene group may also contain a phenylene, oxygen, sulfur, aminyl, N-substituted aminyl, carbonyl or thiocarbonyl group; the optional substituents of the said organylene group being preferably such as listed hereinabove with reference to the substituents of an aryl or heteroaryl group R 3 of the linking agent (Li) or being radicals having the formulae (II) or (III) hereinabove or being hydroxyl or mercapto groups, and - each Z independently represents hydrogen or -CHR 5 -Q or -CO-CHR5-Q or -CHR 5 -CHR'
  • V is preferably -CH 2 -CH 2 -, -CO-CH2-, -(CH 2 )2-NH-(CH 2 )2- or -(CH 2 )2-N(-Z)-(CH 2 ) 2 -.
  • chelating agents CA having one or more aminyl Z substituents independently selected from thioethyl and derivatives thereof (-CH 2 CH 2 SR 4 ), -COCH2SR4, thiomethyl and derivatives thereof (-CH 2 SR 4 ), the remaining aminyl Z substituents being preferably selected from hydrogen, phosphonomethyl, carboxymethyl and derivatives thereof, carboxyethyl and derivatives thereof, hydroxyethyl and derivatives thereof such as previously defined (and including -CH 2 CH 2 OR 4 ). Additionally, one or more of the remaining aminyl Z substituents may represent a heterocyclic group such as previously indicated. Suitable examples thereof include the following:
  • ethylene dicysteine ethylene cysteine cysteamine, cysteinylglycine cysteine, bismercaptoacetyldiaminopropionic acid, bismercaptoacetyldiaminosuccinic acid, bismercaptoacetyldiaminobutyric acid, N-(mercaptoacetylamino- ethyl)cysteine, dimercaptosuccinic acid, dimercaptopropionic acid, cysteine, cysteamine, diphosphinopropionic acid, and derivatives thereof wherein one or more thiol functions are protected by a suitable R 4 group such as defined hereinabove.
  • the latter chelating agents are preferred namely when the complexing metal used is technetium-99m, rhenium-186 or rhenium-188.
  • V is preferably -CH 2 -CH 2 -, -(C 5 H 8 )-, -(C 6 ,H ⁇ 0 )-, -(CH 2 ) 2 -NH-(CH 2 )2- or -(CH 2 )2-N(-Z)-(CH 2 ) 2 -, and the integer a in formula (V) is preferably 0 or 1.
  • preferred chelating agents have two or more, preferably three to five, aminyl Z substituents each independently selected from the group consisting of carboxymethyl (-CH2COOR4) and derivatives thereof (-CHR 5 COOR 4 ), carboxyethyl (-CH 2 CH 2 COOR 4 ) and derivatives thereof (-CHR 5 CHR' 5 COOR 4 ).
  • Remaining aminyl Z substituents are preferably each independently selected from hydrogen, phosphonomethyl, carboxymethyl and derivatives thereof, carboxyethyl and derivatives thereof, hydroxyethyl and derivatives thereof (such as previously defined), methylamido (-CH2CO-NH2) or derivatives thereof (-CH 2 CO-NH-R 4 and -CH 2 CO-NR 4 R' 4 ), ethylamido (-CH 2 CH 2 CO-NH 2 ) or derivatives thereof (-CH 2 CH 2 CO-NHR and -CH 2 CH 2 CO-NR 4 R' 4 ), methylhydrazido (-CH 2 CO-NH-NHR 4 and
  • aminyl Z substituents can represent a straight-chain or branched-chain saturated or unsaturated alkyl group optionally substituted by halogen atoms and/or functional groups and optionally comprising a saturated, unsaturated or aromatic heterocyclic group comprising one or more heteroatoms and optionally bearing up to 3 independently selected substituents, such as for instance (furfuryl)alkyl, (hydroxyfurfuryl)alkyl, (imidazolyl)alkyl, (methylimidazolyi)alkyl, benzyl, benzyloxymethyl, 4-carboxymethoxybenzyl, 4-methoxybenzyl, 4-ethoxy- benzyl, 4-butoxybenzyl, 4-benzyloxybenzyl, 4-(
  • Chelating agents CA of formulae (IV) and (V) which do not comprise a thiol function preferably have carboxymethyl groups (-CH 2 COOR 4 wherein * is as defined above) as the predominant aminyl Z substituents. Suitable examples thereof include:
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylene triaminopentaacetic acid
  • CDTA trans-1 ,2-cyclohexanediamine tetraacetic acid
  • DOTA 1,4,7,10-tetraazacyclododecane tetraacetic acid
  • DOTA 1,4,7-triazacyclononanetriacetic acid
  • TETA 1-tetraazacyclotetradecanetetra-acetic acid
  • EGTA ethyleneglycol- O,O'-bis(2-aminoethyl)tetraacetic acid
  • HBED N,N- bis(hydroxybenzyl)ethylenediamine-N,N'-diacetic acid
  • TTHA triethylenetetramine hexaacetic acid
  • HEDTA hydroxyethyldiamine triacetic acid
  • HEDTA 1,5,9-triazacyclo-dodecanetriacetic acid
  • - analogues of the above compounds wherein one or more carboxymethyl groups are replaced by hydrogen and/or by another aminyl Z substituent in such a way that Z together with the aminyl group to which it is attached comprises one of the following: aminoethanol,
  • amino-acids such as glycine
  • Suitable examples of such analogues include N-(2-hydroxyethyl) diethylenetriamine N,N',N",N'" tetraacetic acid and N-(2-hydroxyethyl) ethylenediamine N,N',N" triacetic acid.
  • chelating agents CA of formulae (IV) and (V) especially preferred are those having structures represented by any of the following formulae 10a-10g and 11a-11b: Formula 10a Formula 10b Formula 10c
  • the optional spacing agent (Sp) which may be present in the metal- complexing substituents Ci and/or C2 is preferably a radical represented by the formula -(X) t -(Sp')-, wherein t is 0 or 1 , (Sp') is derived from a molecule bearing:
  • a carboxylic acid function e.g. acid, acid halide or acid ester
  • X is a carboxy group or a primary or secondary amino group.
  • preferred spacing agents are radicals derived from bis-amines, such as preferably hydrazine, or from amino-acids, such as detailed hereinafter in the context of the methods for producing the novel compounds of the invention.
  • the optional substituents Ri and/or R 2 which may be present on the phenyl ring of the indolyl groups may be each independently selected for instance from the following list:
  • halogen atoms such as fluoro, chloro, iodo and bromo
  • - branched chain alkyl groups of 3 to 8 carbon atoms such as isopropyl, isobutyl, tert-butyl, isoamyl, methylpentyl, 2-ethylhexyl and the like, - cycloalkyl groups of 3 to 7 carbon atoms, in particular cyclopentyl and cyclohexyl, - straight chain and branched chain alkoxy groups of 1 to 6 carbon atoms such as methoxy, ethoxy, propyloxy, buyloxy and amyloxy,
  • ester group derives from an alkyl group having 1 to 4 carbon atoms (such as above defined), and
  • the Ri and/or R 2 substituents are preferably substituents which are not easily oxidable. Therefore, hydroxyl and mercapto groups and other functional groups similarly susceptible of causing oxidation of the compounds of the invention and consequently susceptible of causing a significant discoloration of physiologically acceptable solutions containing the said compounds should preferably be avoided.
  • the single bond or linking agent L covalently links together the carbon atoms being respectively in positions 2 or 3 and 2' or 3' (using conventional nomenclature rules) on the heterocyclic rings of the indolyl groups of the bis-indole derivatives of the invention.
  • L, Ci, C 2 , Ri, R 2 , R3, p, q and r are as defined hereinabove, a sub-family wherein L covalently links the carbon atoms being respectively in positions 2 and 2', having the structure shown in formula (lb) hereunder:
  • L, C-i, C 2 , Ri, R 2 , R 3 , p, q and r are as defined hereinabove, and A and B designate the heterocyclic rings of the indolyl groups, and a sub-family wherein L covalently links the carbon atoms being respectively in positions 2 and 3'.
  • Exemplary useful and readily available metal-complexable substituted bis- indole derivatives corresponding to formula (la) are for instance selected from the group consisting of:
  • Such salts include sodium and potassium salts and tertiary ammonium salts NR 4 R' 4 R" 4 R'" (wherein R4, R'4, R' and R'" are each independently selected within the meaning of R 4 provided hereinabove under the heading of radicals Z' of the chelating agents). More particularly useful are the sodium salts of:
  • enantiomers means each individual optically active form of the compound of the invention, having an optical purity (as determined by methods standard in the art) of at least 80%, preferably at least 90% and more preferably at least 98%.
  • the said bis- indole compound optionally comprising one or two reactive groups in ⁇ -position with respect to L is first prepared by a coupling reaction involving (i) one mono-indole or two different mono-indoles each optionally comprising one reactive group, the said reactive group being preferably a carboxylic group (for instance a carboxylic acid, a carboxylic acid halide or a carboxylic alkyl ester group) or an amine, and (ii) an aldehyde comprising the moiety (Li),
  • step (b) at least one reactive group, if not already present on the bis-indole compound from step (a), is introduced onto the heterocyclic ring of at least one indolyl group of the said bis-indole compound, in ⁇ -position with respect to L, the said reactive group being preferably a carboxylic group (for instance a carboxylic acid, a carboxylic acid halide or a carboxylic alkyl ester grou) or an amine,
  • a carboxylic group for instance a carboxylic acid, a carboxylic acid halide or a carboxylic alkyl ester grou
  • step (c) the reactive group(s) mentioned in step (a) or step (b) is (are) optionally reacted, usually by a coupling reaction, with at least one spacing agent Sp such as previously defined (i.e. bearing at least two functional end groups) and
  • step (d) the second functional end group of the spacing agent Sp is reacted, usually by a coupling reaction, with a suitable chelating agent CA, such as previously defined, or a chelating agent precursor being able to introduce the desired chelating moiety into the metal-complexable derivative of the invention.
  • a suitable chelating agent CA such as previously defined
  • a chelating agent precursor being able to introduce the desired chelating moiety into the metal-complexable derivative of the invention.
  • the mono-indoles and the coupling reaction conditions of step (a) are well known in the art, the same cannot be said of the 2,3-disubstituted bis-indole intermediates or precursor compounds obtained after step (b) and/or after step (c), which are novel chemical compounds having utility in the preparation of the metal-complexable derivatives of the invention.
  • a first class of novel precursor compounds for the metal-complexable substituted bis-indole derivatives of formula (I) consists of compounds obtained after step (c), being 2,3-disubstituted bis-indole compounds optionally having one or more spacing agents (Sp) attached, in ⁇ -position which with respect to L, to the heterocyclic ring(s) of the indolyl group(s).
  • this first class of novel precursor compounds are the bis-hydrazides (3'- ⁇ [(2-hydrazinocarbonyl)-1 H-indol-3-yl]-phenyl-methyl ⁇ -1 H- indole-2-carbonyl)-hydrazine and (3'- ⁇ [(2-hydrazinocarbonyl)-1 H-indol-3-yl]- methyl ⁇ -1 H-indole-2-carbonyl)-hydrazine, their indol-2-yl isomers (i.e., using trivial names, 3,3'-benzylidenebis(indole-2-carboxylic acid hydrazide) and 3,3'- methylenebis (indole-2-carboxylic acid hydrazide) and analogues thereof.
  • analogues makes reference to similar compounds wherein (i) the phenyl ring of each indolyl group may be independently substituted with substituents Ri and/or R 2 such as previously defined for the derivatives of formula (I) and/or wherein (ii) the methylene or benzylidene bridging group between the indolyl groups may be replaced with a single bond or with any other linking agent (Li) such as previously defined for the derivatives of formula (I) and/or wherein (iii) hydrazine is replaced by another bis-amino or amino-acid radical, as defined hereinafter.
  • substituents Ri and/or R 2 such as previously defined for the derivatives of formula (I) and/or wherein (ii) the methylene or benzylidene bridging group between the indolyl groups may be replaced with a single bond or with any other linking agent (Li) such as previously defined for the derivatives of formula (I) and/or wherein (iii)
  • X and each of Spi and Sp2 respectively have the meaning of X and Sp' given hereinabove.
  • This first class of precursor compounds may be readily prepared during step (c) by reacting a spacing agent - such as hydrazine, a bis-amine or an amino- acid - with a bis-indole compound comprising at least one group reactive with the first functional end group of the said spacing agent Sp, for instance a 2,3- disubstituted carboxylated bis-indole such as 3'- ⁇ [(2-alkyloxycarbonyl)-1H-indol- 3-yl]-phenyl-methyl ⁇ -1H-indole-2-carboxylic acid ethyl ester, their indol-2-yl isomers and analogues thereof wherein (i) the phenyl ring of each indolyl group may be independently substituted with substituents Ri and/or R 2 such as previously defined and/or wherein (ii) the methylene or benzylidene bridging group between the indolyl groups may be replaced with a single bond or with
  • the latter may be referred as a second class of novel precursor compounds, being intermediates useful for the preparation of the precursors of the first class.
  • These 2,3- disubstituted carboxylated bis-indoles in turn can be suitably prepared either according to step (b) or by another procedure comprising coupling one or more mono-indole compounds, at least one of them bearing a carboxylic group- containing substituent (for instance a carboxylic acid, a carboxylic acid halide or a carboxylic alkyl ester group) or an amino-containing substituent (for instance an alkylene amine -(CH 2 ) n -NH 2 ,) in ⁇ -position or ⁇ -position (depending whether a compound of formula (la) or a compound of formula (lb) is desired in the final step) with respect to the nitrogen atom of the indolyl group, by means of a known coupling agent.
  • a carboxylic group- containing substituent for instance a carboxylic acid
  • Suitable coupling agents for this purpose include aromatic and heteroaromatic aldehydes (an extensive list of which has been provided hereinbefore) or formaldehyde, thus yielding homodimeric or heterodimeric (i.e. symmetric or not) bis-indole carboxylic acid or bis-indole amino compounds, depending on whether one or two different mono-indole compounds were used in the said coupling reaction.
  • the second class of precursor compounds comprise the structure shown in formula (IX) hereunder:
  • a spacing agent (Sp) can be introduced into the bis-indole molecule during step (c) in various ways. These include for example the modification of one or more available W substituents as shown in formula (VII) hereinafter or the introduction of one or more new W substituents and/or combinations thereof. Again, use can be made of compounds referred to as homobifunctional spacing agent precursors (optionally with one or more function(s) in a protected form) or their heterobifunctional analogues in an optionally protected form.
  • Analogues of the bis-hydrazide precursors of the first class are compounds for the preparation of which hydrazine is replaced with:
  • a bis-amine for instance selected from alkyl diamines having the formula NH 2 -(CH 2 ) 2 -1 2 -NH 2 including 1 ,2-diaminoethane, 1 ,5-diaminopentane
  • alkyl diamines comprising one or more hetero atoms such as for example 1 ,8-diamino-3.6-dioxaoctane, 1 ,5-diamino-3-oxapentane; alkyl diamines comprising one or more optionally protected functional groups such as for example lysine and lysine ; cyclic bis-amines such as for example piperazine and derivatives thereof; or
  • an amino-acid whether naturally-occurring or not, including a straight chain or branched chain hydrocarbon group with 1 to 6 carbon atoms.
  • a chelating agent CA can be introduced during step (d) of the preparation process, either directly or indirectly by making use of a precursor CA compound.
  • precursor CA compounds include but are not restricted to the well-known bi-functional chelating agents which, beside the functional groups (most often shielded by protective groups) necessary for metal complexation, bear a functional group (most often in an activated form, e.g. carboxylic acid esters comprising an appropriate leaving group) that can be specifically used in conjugation reactions.
  • a bi-functional chelating agent is useful for introducing one or more CA functions into the bis-indole molecule. This can be accomplished by conjugating the bi-functional chelating agent directly to an atom which is part of the indolyl groups or the spacing agent (Sp), for example the nitrogen atom of a primary or secondary amine.
  • step (d) involves an amine on the precursor compound of the first class (i.e. a bis-indole/spacing agent conjugate) or in case the bis-indole contains one or two amino-containing substituents on the heterocyclic rings of the bis-indoles, then a carboxylic acid group (or its activated form) of the chelating agent CA is usually involved in the coupling procedure, as is the case for instance in bi-functional chelating agents bearing an intra-molecular anhydride such as those derived from an iminodiacetic acid molecule portion (-N(CH 2 COOH) 2 ).
  • Exemplary compounds of this kind comprise the bis- anhydrides of EDTA, DTPA and the like (such as disclosed in French Patent No.
  • DTPA monoanhydride mono-ethyl ester as well as the DTPA monoanhydride mono-ethyl ester.
  • the latter compound may suitably be prepared from DTPA monoethyl ester by reacting with acetic anhydride in the presence of pyridine.
  • Other bi-functional DTPA derivatives are known from the literature (see e.g. J. Org. Chem. (1990) 55:2868 and U.S.Patent No. 5,514,810).
  • step (d) involves an amine on the chelating agent CA
  • one or two carboxylic acid groups (or their activated form) of the precursor compound of the first class i.e. a bis-indole/spacing agent conjugate
  • the precursor compound of the first class i.e. a bis-indole/spacing agent conjugate
  • the present invention includes a novel method for obtaining monoreactive mono-anhydrides comprising the structural formula VI in figure 1 via an intermediate which facilitates their purification.
  • Such intermediate may be a monobenzyl ester obtained by reacting the corresponding bis-anhydride having the formula 1 shown at top of figure 1 with benzyl alcohol in the presence of a suitable reagent such as for example water, ammonia, primary or secondary amines, hydrazides or alcohols, such as detailed hereinafter.
  • the indicia s, t, u and v are each independently selected integers from 1 to 3, provided that the sum of s and t is not above 4 and that the sum of u and v is not above 4;
  • - V is an organylene group such as described in detail in respect of formulae (IV) and (V) hereinabove;
  • U x and U y are freely but mutually exclusively selected from either the group comprising -OH and -O " Cat + , wherein Cat + is an organic cation, e.g. a carboxylic acid ammonium, sodium, calcium or potassium salt, or the group comprising aminyl radicals of formula -NH 2 or substituted derivatives thereof and ether-type radicals, i.e. U x and U y together with the neighbouring carbonyl group may be a carboxylic acid, a carboxylic acid salt, an (optionally N,N- or N-substituted) amide, a hydrazide or a bis acylhydrazide group.
  • Cat + is an organic cation, e.g. a carboxylic acid ammonium, sodium, calcium or potassium salt, or the group comprising aminyl radicals of formula -NH 2 or substituted derivatives thereof and ether-type radicals, i.e. U x and U y together with the neighbour
  • the bis-anhydride analogue of formula 1 in figure 1 obtained for instance according to the method of French Patent No. 1 ,548,888, is dissolved (with optional heating) in a suitable anhydrous solvent (for example dimethylformamide) in the presence of a base which does not react with anhydrides (for example a tertiary amine such as triethylamine).
  • a suitable anhydrous solvent for example dimethylformamide
  • anhydrides for example a tertiary amine such as triethylamine
  • anhydrides for example a tertiary amine such as triethylamine
  • anhydrides for example a tertiary amine such as triethylamine
  • anhydrides for example a tertiary amine such as triethylamine
  • anhydrides for example a tertiary amine such as triethylamine
  • the reagent is preferably selected from amino, hydrazo and hydrazido compounds. Even when reaction conditions are optimal with respect to temperature, dilution and method of introduction of reactants, a substantial amount of by-products will be present.
  • a second step involves the physical separation of the major reaction products. Selecting an alcohol comprising one or more aromatic groups in the first step enables purification to proceed under milder conditions, i.e. for example non-hydrolytic conditions with respect to lower alkyl esters) by using methods that allow separation based on differences in hydrophobicity and type of hydrophobic interaction.
  • a chelating agent function CA can be introduced into a precursor compound of a bis-indole derivative of formula (I) at any stage of the synthesis.
  • it may be introduced previously to condensing the indolyl groups, although it is more often advantageous and easier to introduce it at a later stage, as explained hereinabove.
  • Exemplary novel precursor compounds according to the invention comprise the structure shown in formula (VII) hereunder:
  • - L, m, n, p, q and r are all as defined in formula (I) hereinabove, and - Wi and W 2 are optional substituents which, optionally after adequate chemical modification, enable the attachment of metal-complexing substituents such as Ci and C 2 of formula (I) respectively, and being at position 2 or 2' (when L is at position 3 or 3') or at position 3 or 3' (when L is at position 2 or 2') of each indolyl group, i.e. in ⁇ position with respect to L.
  • the precursor compounds of formula (VII) are preferably symmetric with regard to the indolyl groups, however due to the occurrence of possibly different substituents on the phenyl ring of the indolyl groups, and possibly due to the linking agent (Li), they may also be asymmetric.
  • substituted bis-indole derivatives having the structure shown in formula (I) are obtained from the first class of novel precursor compounds of this invention.
  • a (second class) precursor compound bearing a carboxylic ester function such as e.g. a 3'- ⁇ [(2-alkyloxycarbonyl)-1 H-indol-3-yl]-phenyl-methyl ⁇ - 1 H-indole-2-carboxylic acid ester
  • a carboxylic ester function such as e.g. a 3'- ⁇ [(2-alkyloxycarbonyl)-1 H-indol-3-yl]-phenyl-methyl ⁇ - 1 H-indole-2-carboxylic acid ester
  • aminolysis e.g.
  • chelating agents CA including those cited in formulae 10a to 10g, 11a and 11b hereinabove, can be easily introduced into the final bis-indole derivative having the structure of formula (I).
  • a multitude of specific substituted bis-indole derivatives each embodying the structure of formula (I), may be produced which may exhibit some quantitative differences with respect to their properties in medical applications, such as blood clearance (ranging from relatively fast to relatively slow), elimination from the body (predominantly by kidney or shifted to hepatobiliary secretion), plasma protein binding (from low to high), etc.
  • Labeling/complexation of the substituted bis-indole derivatives according to formula (I) can be accomplished, using methods well known in the art, by chelation with radioactive or non-radioactive metal ions, preferably with ions of an element with an atomic number selected from 21 to 32, 37 to 39, 42 to 44, 49, 50 or 57 to 83 such as for example:
  • Chelation with metal ions can be performed by methods well documented in the literature, i.e. at any stage of the production, although most often in the final step.
  • protected functional groups When protected functional groups are present in the metal-complexing substituents, they may be partly or completely deprotected prior to metal chelation.
  • lonizable groups not involved in metal complexation may be optionally neutralized by acidic or basic counter-ions or by (inorganic and/or organic) compounds bearing ionizable acidic and/or basic groups.
  • Remaining acidic protons i.e. those that have not been substituted by the metal ion, can optionally be completely or partially replaced by cations of inorganic or organic bases, basic amino-acids or amino-acid amides.
  • Suitable inorganic counter ions are for example the ammonium ion, the potassium ion, the calcium ion, the magnesium ion and, more preferably, the sodium ion.
  • Suitable cations of organic bases are, among others, those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, tris(hydroxymethyl)aminomethane and especially N-methylglucamine.
  • Suitable cations of amino-acids are, for example, those of lysine, arginine and omithine as well as the amides of any other acidic or neutral amino-acid such as for example lysine methylamide, glycine ethylamide or serine methylamide.
  • the above-described substituted bis-indole derivatives of formula (I) and their metal complexes may be used in vitro, in vivo and/or ex vivo, for instance in the form of their pharmaceutically acceptable salts and/or in the form of pharmaceutical compositions comprising them in admixture with at least one pharmaceutically acceptable carrier, as diagnostic agents and/or therapeutic agents.
  • these active ingredients are useful for the manufacture of medicaments suitable for imaging or imaging-aided applications, including magnetic resonance imaging (MRI), nuclear scintigraphy (NS), MRI-aided applications or NS-aided applications or for the manufacture of imaging agents or imaging-aided agents for use in such applications.
  • in vivo effective contrast agents including multipurpose contrast agents, for visualizing and/or identifying organs, parts of organs or systems such as for example the vasculatory system, the hepatobiliary system or the renal-urinary system, tissues such as for example necrotic tissue, and for visualizing and/or identifying diseases and pathologies.
  • Diseases involved in this aspect of the invention include ischemic insults such as myocardial or cerebral infarction and space-occupying lesions (e.g. tumors or inflammatory lesions) in solid organs such as the liver, kidney, spleen, adrenal gland, etc. These agents are also useful in the follow-up of a therapy, for instance the evolution of necrosis.
  • these contrast agents are useful in medical applications involving necrosis and necrosis-related pathologies, such as pathological or therapeutic necrosis caused by pathologic or therapeutically-induced ischemia or originating from trauma, radiation and/or chemicals, including therapeutic ablation, radiotherapy and/or chemotheraphy, myocardial and cerebral infarctions.
  • necrosis and necrosis-related pathologies such as pathological or therapeutic necrosis caused by pathologic or therapeutically-induced ischemia or originating from trauma, radiation and/or chemicals, including therapeutic ablation, radiotherapy and/or chemotheraphy, myocardial and cerebral infarctions.
  • they are administered to the human body, preferably enterally or parenterally, as therapheutic and/or diagnostic agents.
  • a suitable formulation is a physiologically acceptable liquid formulation, preferably an aqueous solution or an emulsion or suspension including conventional surfactants such as polyethylene glycol.
  • the invention in an another embodiment, relates to a method for generating an image of at least a part of a body of a mammal, comprising systemically or locally administering to the mammal a contrast agent effective amount of a metal-complexable substituted bis-indole derivative or a metal complex thereof having the formula (I).
  • the contrast agents of the invention are used systemically as diagnostic agents by parenteral administration, including intravenous injection, at low doses, i.e. when a complexing metal such as gadolinium is used, i.e.
  • the contrast agents of the invention are also useful for local administration, e.g. including intracoronary administration in the case of a patient with myocardial infarction.
  • an effective local dose of the contrast agent of the invention may be from 1 to about 5 ⁇ moles gadolinium per kg body weight of the patient to be treated.
  • the metal complex when a radioactive complexing metal such as indium-111 is used, the metal complex may be administered with a radioactivity in the range of about 20 to 200 MBq (megabecquerels). When a radioactive complexing metal such as technetium-99 is used, the metal complex may be administered with a radioactivity in the range of about 350 to 1 ,000 MBq.
  • DTPA diethylene triamine pentaacetic acid
  • TAA dry triethylamine
  • Example 2 preparation of DTPA monoethyl ester
  • DTPA monoethyl ester was prepared by hydrogenolysis of the purified compound obtained in example 1 by dissolving it in 350 ml of a 70% ethanol/30% water mixture (volume/volume), then adding 2 g palladium on activated carbon (Pd 10%). After 5 hours of a hydrogen gas treatment under a 20 p.s.i pressure, charcoal was removed by filtration over a thin path of Celite. The residue was then washed with the same warm ethanol/water mixture. Solvents from the combined filtrate and washings were removed under reduced pressure. Drying in vacuum over P2O 5 afforded 27 g of DTPA monoethyl ester.
  • the title compound was prepared from commercially available benzaldehyde and indole-2-carboxylic acid in a 90% yield, following the procedure disclosed by Granacher et al. in Helv. Chim. Ada (1924) 7:579-586.
  • Example 6 preparation of ⁇ 4.7-Bis-carboxymethyl-10-[( ⁇ 3-[i2- ⁇ N'-[(4.7.10-tris- carboxymethyl-1.4,7.10-tetraaza-cyclododec-1 -yl)-acetyl]-hydrazinocarbonyl)- 1 H-indol-3-yl)-methyl]-1 H-indole-2-carbonyl ⁇ -hvdrazino)-2-oxo-ethyl]-1.4.7.10- tetraaza-cyclododec-1-yl ⁇ -acetic acid sodium salt (first methodl)
  • Example 7 preparation of ⁇ 4.7-bis-carboxymethyl-10-[f ⁇ 3-[(2- ⁇ N (4.7.10-tris- carboxymethyl-1.4.7.10-tetraaza-cvclododec-1 -ylVacetylj-hydrazinocarbonyl ⁇ - 1 H-indol-3-v ⁇ -methyl]-1 H-indole-2-carbonyl ⁇ -hydrazino)-2-oxo-ethyl]-1.4.7.10- tetraaza-cyclododec-1-yl ⁇ -acetic acid sodium salt (second method).
  • Example 8 preparation of the bis gadolinium complex of ⁇ 4.7-Bis- carboxymethyl-10-[( ⁇ 3-[(2- ⁇ N'-[(4.7.10-tris-carboxymethyl-1.4.7.10-tetraaza- cyclododec-1 -yl)-acetyl]-hydrazinocarbonyl ⁇ -1 H-indol-3-yl)-methyl]-1 H-indole-2- carbonyl ⁇ -hydrazino)-2-oxo-ethyl]-1.4.7.10-tetraaza-cyclododec-1-yl ⁇ -acetic acid
  • Gadolinium acetate was incrementally added to an aqueous solution of the compound of example 6. After each addition the pH was adjusted to 7.4 by means of NaOH (1.0 M). Formation of mono- and bis-gadolinium chelates was monitored by HPLC, knowing that chelation increases retention time. Addition of gadolinium acetate was stopped when the compound was virtually completely converted into the bis- and mono- gadolinium complexes, the latter amounting to minor amounts (DTPA moieties not involved in gadolinium complexation was less than 10%). Identity of the complex was confirmed by mass spectrometry on a Micromass LCT instrument (time of flight) with electrospray ionisation detection. Peaks are present at 1497 dalton (i.e.
  • Example 9 preparation of-3'- ⁇ [(2-alkyloxycarbonyl)-1 H-indol-3-yl]-methyl ⁇ -1 H- indole-2-carboxylic acid ethyl ester.
  • the title compound was prepared from formaldehyde and indole-2- carboxylic acid in a 28% yield, following the procedure disclosed by Granacher et al. in Helv. Chim. Ada (1924) 7:579-586.
  • Example 11 preparation of 2-fN'-(3- ⁇ [2- ( N'- ⁇ 2-r(2-(r2-bis(carboxymethyl- amino)-ethyl]carboxymethylamino ⁇ -ethy ⁇ carboxymethyl-amino]-acetyl ⁇ - hydrazinocarbonyl)-1 H-indol-3-yl]-methyl ⁇ -1 H-indole-2-carbonyl)-hydrazino]-2- oxo-ethyl ⁇ -(2- ⁇ [2-bis(carboxymethyl-amino)-ethyl1-carboxymethylamino ⁇ -ethyl)- aminoj-acetic acid sodium salt
  • Preparation was effected as described in example 6 but starting from 6.33 g of the compound of example 10, yielding the desired sodium salt in a 70% yield. Its identity was confirmed by mass spectrometry on a Micromass LCT instrument (time of flight machine) with electrospray ionisation detection, yielding a peak
  • Example 12 preparation of the bis gadolinium complex of [ ⁇ 2-[N'-(3- ⁇ [2-(N'- ⁇ 2- [(2- ⁇ [2-bis(carboxymethyl-amino)-ethyl]carboxymethylamino ⁇ - ethyl)carboxymethyl-amino]-acetyl ⁇ -hydrazinocarbonyl)-1H-indol-3-yl]-methyl ⁇ - 1 H-indole-2-carbonyl)-hydrazino]-2-oxo-ethyl ⁇ -(2- ⁇ [2-bis(carboxymethyl-amino)- ethyl]-carboxymethylamino ⁇ -ethyl)-amino]-acetic acid sodium salt.
  • the compound of example 11 (12.0 g, 10 mmole) was dissolved in 200 ml water; a solution of 11.5 mmole of gadolinium acetate Gd(0Ac) 3 .3H 2 0 in 100 ml of water was then slowly added while maintaining the pH at 7 with 25% NH 3 .
  • the Gd-complex was evaporated to dryness, washed with acetonitrile and dried under vacuum over phosphorus pentoxide and sodium hydroxide for removing ammonium acetate. 13.25 g (90%) of the title complex was obtained.
  • Example 13 - preparation of 4.7-Bis-carboxymethyl-10-[( ⁇ 3-[(2- ⁇ N'-[(4.7.10-tris- carboxymethyl-1.4.7.10-tetraaza-cvclododec-1 -yl)-acetyl]-hydrazinocarbonyl ⁇ - 1 H-indol-3-yl)-phenyl-methyl]-1 H-indole-2-carbonyl ⁇ -hydrazino)-2-oxo-ethyl]- 1.4.7.10-tetraaza-cyclododec-1-yl ⁇ -acetic acid 1 ,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA, 8.08 g, 20 mmole) was dissolved in a mixture of 15 ml of ammonia and 250 ml of dry DMSO by stirring and sonicating.
  • DOTA 1, 8.08 g, 20 mmole
  • Example 14 preparation of 3.3'- p-methoxybenzylidenebis(indole-2-carboxylic acid ethyl ester) 3'- ⁇ [(2-alkyloxycarbonyl)-1 H-indol-3-yl]-(4-methoxyphenyl)- methy! ⁇ -1 H-indole-2-carboxylic acid ethyl ester
  • the title compound was prepared, from 4-methoxybenzaldehyde and indole-2-carboxylic acid in a 85 % yield, following the procedure disclosed by Granacher et al. in Helv. Chim. Ada (1924) 7:579-586.
  • Example 16 preparation of ⁇ 2-[N'-(3- ⁇ [2-(N'- ⁇ 2-[(2- ⁇ [2-bis(carboxymethyl- amino)-ethyl]carboxymethylamino ⁇ -ethyl)carboxymethyl-amino]-acetyl ⁇ - hydrazinocarbonyl)-1 H-indol-3-yl1-(4-methoxyphenyl)-methyl ⁇ -1 H-indole-2- carbonyl)-hydrazino]-2-oxo-ethyl ⁇ -(2- ⁇ [2-bis(carboxymethyl-amino)-ethyl]- carboxymethylamino ⁇ -ethyl)-amino]-acetic acid sodium salt.
  • Example 17 preparation of the bis gadolinium complex of [ ⁇ 2-[N'-(3- ⁇ [2-(N'- ⁇ 2- [(2- ⁇ [2-bis(carboxymethyl-amino)-ethyl]carboxymethylamino ⁇ - ethyl)carboxymethyl-amino]-acetyl ⁇ -hydrazinocarbonyl)-1H-indol-3-yl]-(4- methoxyphenyl)-methyl ⁇ -1 H-indole-2-carbonyl)-hydrazinol-2-oxo-ethyl ⁇ -(2- ⁇ [2- bis(carboxymethyl-amino)-ethyl]-carboxymethylamino ⁇ -ethyl)-amino]-acetic acid sodium salt.
  • the compound of example 16 was quantitatively converted to its bis- gadolinium complex by following essentially the same procedure as described in example 8. Identity of the complex was confirmed by mass spectrometry on a Micromass LCT instrument (time of flight) with electrospray ionisation detection. Peaks are present at 763 dalton (half of the molecular mass, corresponding to the bis-anionic compound) and 508 dalton (one third of the molecular mass: compound with three negative charges). Both peaks show the characteristic distribution of the different stable isotopes of gadolinium.
  • Example 18 preparation of the indium-111 complex of [ ⁇ 2-[N'-(3- ⁇ [2-(N'- ⁇ 2-[(2- ⁇ [2-bis(carboxymethyl-aminoVethyl]carboxymethylamino ⁇ -ethyl)carhoxymFithyl- amino]-acetyl ⁇ -hydrazinocarbonyl)-1 H-indol-3-yl]-(4-methoxyphenyl)-methyl ⁇ - 1 H-indole-2-carbonyl)-hydrazino]-2-oxo-ethyl ⁇ -(2- ⁇ [2-bis(carboxymethyl-amino)- ethyl]-carboxymethylamino ⁇ -ethyl)-amino]-acetic acid sodium salt
  • MRI parameters were as follows: slice thickness was 2 mm (without gap); the field of view was 7.5 cm x 10 cm, with a matrix of 192 x 256. Two acquisitions were averaged, resulting in a measurement time of about 3 minutes. A glass tube containing 0.02% CuSO 4 solution was placed beside the rat as an external standard for normalization of signal intensity (SI) values. Together with a precontrast T1-w imaging, only one T2-w measurement was performed at the beginning to verify the presence of infarcted liver lobe. Rats were scanned on transverse sections before and after contrast injection of the compound of example 8 at a concentration of 0.05 mmole Gd per kg body weight. Postcontrast T1-w MRI was effected 5 minutes (early phase), 40 minutes and 24 hours (late phase) thereafter.
  • SI signal intensity
  • rats were sacrificed by an intravenous overdose of phenobarbital and placed in a deep freezer (below -20°C) overnight in the same position as that during MR imaging.
  • the frozen rats were sectioned in the transverse plane similar to that on MRI in order to match the imaging and histologic findings.
  • Another approach was to perfuse freshly excercised liver (or other organs) with a 2,3,5-triphenylterazolium solution in order to provoke staining of viable tissue.
  • tissue samples were fixated, sectioned, stained and analyzed according to standard procedures.
  • results of MRI-imaging and post mortem macroscopic analysis as shown in figure 3 demonstrate the blood pool effects of the compound of example 8 and its ability to visualize necrosis.
  • the infarcted liver lobe (arrow) is almost isointense relative to the normal liver (A).
  • the signal intensity of normal liver is enhanced and the infarcted lobe (arrow) remains hypointense. All intrahepatic vessels exhibit strong signal intensity, a feature characterizing the reperfused infarction model.
  • Example 20 in vivo test of rat liver infarction at low dose
  • example 8 used in an appropriate dilution, by means of saline buffer, of a preparation of 350 mM Gd
  • One group of rats received a dose of about 50 ⁇ mole gadolinium per kg body weight (as in example 19) while the other group received a dose of about 10 ⁇ mole gadolinium per kg body weight.
  • the observed ratio between normal and necrotic liver was equal to or higher than 1.3 in rats who received the 10 ⁇ mole Gd/kg dose. In rats who received the 50 ⁇ mole Gd/kg dose, this ratio was greater than 1.6.
  • the agent is cleared rather slowly and that normal liver is involved in eliminating the complex from the body, and that 24 hours after injection there is still enhancement in normal liver on MRI images, therefore when infarction is located in the myocardium or the brain, or more generally in organs and/or tissues not involved in elimination of the complex, the contrast ratio will be still much higher. Accordingly, doses below 15 ⁇ mole Gd/kg will be effective in vivo when the complex is used in systemic applications. When the site of necrosis permits local administration of the agent (such as for example intracoronary administration in the case of myocardial infarction), then doses far below those effective in systemic applications can be used.
  • Example 21 in vivo test of rat liver infarction with delayed administration
  • the compound of example 8 was further tested in the same rat model of reperfused liver infarction as described in example 8 at normal dose (about 50 ⁇ mole Gd/kg) and low dose (about 15 ⁇ mole Gd/kg), but administering the said compound after a delay of 48 hours following inducing the liver infarction.
  • Pigs weighing about 40 kg were sedated with intramuscular xylazine (commercially available under the tradename Rompun from Bayer) at 2.5 ml/kg, anesthetized with an intravenous bolus of 60 mg of sodium pentobarbital (Nembutal, Sanofi), intubated and ventilated on a positive pressure ventilator. Anesthesia was maintained by dosed infusion of sodium pentobarbital beneath the level of spontaneous respiration. Myocardial infarction was induced through a surgical procedure.
  • intramuscular xylazine commercially available under the tradename Rompun from Bayer
  • a dose of 0.05 mmole/kg of the compound of example 8 was administered intravenously.
  • Cardiac MRI was performed one, two, four, six and twelve hours respectively after administration on a 1.5 T clinical imager (Siemens Magnetom Vision, Eriangen, Germany) with gradient switching capabilities of 25 mT/m in 300 ⁇ sec. All pigs were positioned in the supine position in the standard surface coil, centered on the xyphoid process of the sternum. MR images were obtained in the true short axis and optionally in the long-axis. Under ventilator-assisted breath-holding, we used an ECG- triggered and segmented single-slice turboFLASH sequence.
  • the sequence starts by applying a 180° inversion pulse for annulling the signal from the cardiac cavity, after which an echo train of 33 echoes is acquired after each R- peak of the ECG. With a matrix of 165 x 256, this results in filling of k-space in 5 heartbeats.
  • Other sequence parameters were: TR/TE/ ⁇ : 7.5 msec/4.3 msec/25 0 , inversion of 600 ms.
  • the field of view was 240 x 320 mm and the slice thickness 6 mm.
  • the animals were sacrificed and the excised heart was stained in a solution of buffered triphenyltetrazolium chloride
  • TTC staining results in red coloration of non- infarcted tissue, whereas necrotic areas exhibit a pale color. All slices were photographed and digitized for morphometry.
  • results of MRI-imaging and post mortem macroscopic analysis as shown in figure 4 demonstrate the effects of the compound of example 8.
  • the infarct appeared isointense and invisible (A).
  • the pale infarcted region (arrow) on TTC histochemically stained section confirmed the above MRI finding (D).
  • MR angiographic images of a rabbit were taken (shown in figure 5) after intravenous injection of:
  • Gd-DTPA commercially available under the tradename Magnevist® from Schering AG, Berlin, Germany
  • A-C 0.1 mmole per kg bodyweight
  • the liver of Wistar rats was implanted with a cube (1x1x1 mm 3 ) of freshly harvested R1 rhabdomyosarcoma tissue.
  • the tumor size grew to 0.8 - 1.2 cm in diameter, ready for radiofrequency ablation (RFA).
  • the RFA protocol was as follows: after anaesthesia, an incision was made along the primary incision for tumor implantation. Under visual inspection, an 18 Gauge cool-tip electrode (Radionics, Burlington, Massachusetts, USA) was directly inserted into the liver tumor. Radiofrequency current was delivered from a RF generator (RFG-3E, available from Radionics) under power control mode at 30W for 20-30 seconds depending on the size of the tumor.
  • RFG-3E radiofrequency generator
  • the ablation volume covered both the entire tumor and a 3-5 mm rim of peritumoral liver parenchyma. After RFA, the electrode was withdrawn and the incision closed. The efficacy of the therapy was evaluated with contrast enhanced MRI, using the compound of example 8 at a concentration of 0.05 mmole per kg bodyweight, and histopathology.
  • Results of MR images (A-E) and cross section (F) of a rat with liver implantation of rhabdomyocarcoma treated with radiofrequency ablation, as shown in figure 6 (A-F), demonstrate the effects of the compound of example 8.
  • the treated tumor (arrow) appeared isointense and invisible (A).
  • the title compound is prepared from the compound of example 28 using the method described in example 5.
  • Example 30 preparation of the bis DTPA conjugate with the bis-hydrazide of 2'-[(3-carboxy-1 H-indole-2yl)-phenyl-methyl]-1 H-indole-3-carboxylic acid
  • the title compound is prepared from the compound of example 29 using the method described in example 6.
  • the title compound is prepared from the compound of example 30 using the method described in example 8.
  • the title compound is prepared from the compound of example 32 using the method described in example 5.
  • Example 34 preparation of the bis-DTPA conjugate of the dihydrazide of 2'-[2- (3-carboxyethyl-1 H-indole-2-yl)-ethyl]-1 H-indole-3'-carboxylic acid
  • the title compound is prepared from the compound of example 33 using the method described in example 6.
  • Example 35 preparation of the bis- ⁇ adolinium complex of the bis-DTPA conjugate of the dihydrazide of 2'- ⁇ r 2-(3-carboxyethyl-1 H-indole-2-v ⁇ -ethyl]-1 H- indole-3'-carboxylic acid
  • Example 36 preparation of the bis-hydrazide of 3'-(2-carboxy-1 H-indole-3- ylsulfanyl)-1 H-indole-2'-carboxylic acid
  • the title compound is prepared starting from 3'-(2-carboxyethyl-1H- indole-3-ylsulfanyl)-1 H-indole-2'-carboxylic acid ethyl ester (the latter being prepared following the procedure described by J. Szmuszkovicsz, J. Org.
  • Example 37 preparation of the bis-DTPA conjugate of the bis-hydrazide of 3'- (2-carboxy-1 H-indole-3-ylsulfanyl)-1 H-indole-2'-carboxylic acid
  • the title compound is prepared from the compound of example 36 using the method described in example 6.
  • Example 38 preparation of the bis-gadolinium complex of the bis-DTPA conjugate of the bis-hydrazide of 3'-(2-carboxy-1 H-indole-3-ylsulfanyl)-1H- indole-2'-carboxylic acid
  • the title compound is prepared from the compound of example 37 using the method described in example 8.
  • Example 39 preparation of the bis-DTPA conjugate of 2'-(3-(2-aminoethyl)- 1 H-indole-2-ylsulfanv ⁇ -1 H-indole-3'-ethyl-2-amine
  • the title compound is prepared from the compound of example 39 using the method described in example 8.
  • Example 42 preparation of the bis-hydrazide of 3'-[2-(3-(2-ethylcarboxyethyl)- 1 H-indole-2-ylsulfanyl)-1 H-indol-3'-yl]-propionic acid
  • the title compound is prepared from the compound of example 41 using the method described in example 5.
  • Example 43 preparation of the bis-DTPA conjugate of the bis-hydrazide of 3'- 2-(3-(2-ethylcarboxyethy ⁇ -1 H-indole-2-ylsulfanvn-1 H-indol-3'yl-]-propionic acid
  • the title compound is prepared from the compound of example 42 using the method described in example 6.
  • Example 44 preparation of the bis-gadolinium complex of the bis-DTPA conjugate of the bis-hydrazide of 2'-(3-(2-ethylcarboxy)-1 H-indole-2-ylsulfanyl)- 1 H-indole-3'-propionic acid
  • the title compound is prepared from the compound of example 43 using the method described in example 8.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Radiology & Medical Imaging (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des dérivés de bis-indole substitué susceptibles d'être complexés par un métal comprenant une structure représentée par la formule (I), des énantiomères, des sels pharmaceutiquement acceptables de ces dérivés, et des complexes métalliques de ceux-ci. Dans cette formule, L, R1, R2, R3, C1, C2, m, n, p, q et r sont tels que définis dans la revendication 1, et sont utilisés comme agents de contraste.
PCT/BE2001/000192 2000-11-08 2001-11-07 Derives de bis-indole substitue utilises comme agents de contraste, compositions pharmaceutiques contenant lesdits derives et intermediaires permettant de preparer ces derives WO2002038546A1 (fr)

Priority Applications (3)

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EP01993601A EP1343758A1 (fr) 2000-11-08 2001-11-07 Derives de bis-indole substitue utilises comme agents de contraste, compositions pharmaceutiques contenant lesdits derives et intermediaires permettant de preparer ces derives
AU2002218075A AU2002218075A1 (en) 2000-11-08 2001-11-07 Substituted bis-indole derivatives useful as contrast agents, pharmaceutical compositions containing them and intermediates for producing them
US10/416,043 US7081472B2 (en) 2000-11-08 2001-11-07 Substituted bis-indole derivatives useful as contrast agents, pharmaceutical compositions containing them and intermediates for producing them

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GB0027249A GB2368843A (en) 2000-11-08 2000-11-08 Non-porphyrin multipurpose contrast agents
GB0027249.2 2000-11-08
GB0120659A GB0120659D0 (en) 2001-08-28 2001-08-28 New generation of multipurpose contrast agents
GB0120659.8 2001-08-28

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003091689A2 (fr) * 2002-03-28 2003-11-06 Rutgers, The State Of University Of New Jersey Sondes a chelates a deux metaux de transition
US20060147551A1 (en) * 2003-01-31 2006-07-06 Hirokazu Uyama Auxiliary agent to be used in cancer therapy by dielectric heating and cancer therapy method
WO2009104198A2 (fr) * 2008-01-25 2009-08-27 Vlife Sciences Technologies Pvt. Ltd. Conjuguès métaliques d'indole 3- aldéhyde azine, et ses dérivés et utilisations
WO2010092114A1 (fr) 2009-02-13 2010-08-19 Guerbet Utilisation de tampons pour la complexation de radionucléides
WO2012084981A1 (fr) 2010-12-20 2012-06-28 Guerbet Nanoemulsion de chelate pour irm
WO2013045333A1 (fr) 2011-09-26 2013-04-04 Guerbet Nanoemulsions et leur utilisation comme agents de contraste
EP2699272A1 (fr) * 2011-04-20 2014-02-26 RF Therapeutics Inc. Agents de contraste et utilisations associées
WO2014114724A1 (fr) 2013-01-23 2014-07-31 Guerbet Magneto-emulsion vectorisee
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US8986650B2 (en) 2005-10-07 2015-03-24 Guerbet Complex folate-NOTA-Ga68
WO2016090491A1 (fr) 2014-12-11 2016-06-16 Rf Therapeutics Inc. Agents de contraste ciblé comprenant un groupe fonctionnel d'hydrazide
WO2020007822A1 (fr) 2018-07-02 2020-01-09 Conservatoire National Des Arts Et Metiers (Cnam) Nanoparticules de bismuth métallique (0), procédé de fabrication et utilisations de celles-ci

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Cited By (18)

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WO2003091689A3 (fr) * 2002-03-28 2004-12-23 Rutgers The State Of Universit Sondes a chelates a deux metaux de transition
WO2003091689A2 (fr) * 2002-03-28 2003-11-06 Rutgers, The State Of University Of New Jersey Sondes a chelates a deux metaux de transition
US20060147551A1 (en) * 2003-01-31 2006-07-06 Hirokazu Uyama Auxiliary agent to be used in cancer therapy by dielectric heating and cancer therapy method
US9056128B2 (en) * 2003-01-31 2015-06-16 Otsuka Pharmaceutical Factory, Inc. Adjuvant used in dielectric heating-assisted cancer treatment, and cancer treatment method
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US8986650B2 (en) 2005-10-07 2015-03-24 Guerbet Complex folate-NOTA-Ga68
WO2009104198A3 (fr) * 2008-01-25 2010-05-06 Vlife Sciences Technologies Pvt. Ltd. Conjuguès métaliques d'indole 3- aldéhyde azine, et ses dérivés et utilisations
WO2009104198A2 (fr) * 2008-01-25 2009-08-27 Vlife Sciences Technologies Pvt. Ltd. Conjuguès métaliques d'indole 3- aldéhyde azine, et ses dérivés et utilisations
WO2010092114A1 (fr) 2009-02-13 2010-08-19 Guerbet Utilisation de tampons pour la complexation de radionucléides
WO2012084981A1 (fr) 2010-12-20 2012-06-28 Guerbet Nanoemulsion de chelate pour irm
US9770520B2 (en) 2010-12-20 2017-09-26 Guerbet Chelate nanoemulsion for MRI
EP2699272A1 (fr) * 2011-04-20 2014-02-26 RF Therapeutics Inc. Agents de contraste et utilisations associées
EP2699272A4 (fr) * 2011-04-20 2014-10-15 Rf Therapeutics Inc Agents de contraste et utilisations associées
WO2013045333A1 (fr) 2011-09-26 2013-04-04 Guerbet Nanoemulsions et leur utilisation comme agents de contraste
WO2014114724A1 (fr) 2013-01-23 2014-07-31 Guerbet Magneto-emulsion vectorisee
WO2016090491A1 (fr) 2014-12-11 2016-06-16 Rf Therapeutics Inc. Agents de contraste ciblé comprenant un groupe fonctionnel d'hydrazide
US10286090B2 (en) 2014-12-11 2019-05-14 Rf Therapeutics Inc. Targeted contrast agents comprising a hydrazide functional group
WO2020007822A1 (fr) 2018-07-02 2020-01-09 Conservatoire National Des Arts Et Metiers (Cnam) Nanoparticules de bismuth métallique (0), procédé de fabrication et utilisations de celles-ci

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US7081472B2 (en) 2006-07-25
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US20040053911A1 (en) 2004-03-18
AU2002218075A1 (en) 2002-05-21
CN1486299A (zh) 2004-03-31

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